Carcinogenesis biomarkers in former smokers of the Multi Ethnic Cohort Study

ABSTRACT Former smokers remain at high risk for lung cancer for years after quitting smoking, with at least 3-fold relative risk compared to never smokers, even 25 years after quitting. More lung cancer cases in the U.S. (50.8%) now occur in former smokers than in current smokers (36.7%), yet we know little about the relevant biochemical mechanisms and related potential biomarkers that could ultimately be used to identify those at high risk. This project proposes to investigate chemical and metabolic biomarkers in former smokers. The Specific Aims are to: 1) Perform a clinical study of inhaled [D10]phenanthrene ([D10]Phe) to determine the ratio of urinary [D10]phenanthrene tetraol ([D10]PheT) to [D9]phenanthrene phenols ([D9]PhOH) as an indicator of increased metabolic activation of PAH in the lungs of former smokers compared to never smokers, possibly due to pleural anthracosis (the accumulation of black particles in the lungs of smokers which persist in former smokers; 2) Perform a clinical study of inhaled [13C18]linoleic acid to determine levels of [13C]mercapturic acids of acrolein, 4-hydroxynonenal and related α,β-unsaturated carbonyl compounds in the urine of former smokers compared to never smokers to investigate the hypothesis that pulmonary inflammation leads to production of these urinary metabolites; 3) Quantify the inflammation and oxidative damage-related adducts 1,N6-etheno-dA, 3,N4-etheno-dC, ɣ-OH- propano-dG, and 8-oxo-dG in DNA from oral cells and leukocytes of former smokers compared to never smokers; and 4) Working together with Core B, quantify biomarkers of potential harm - myeloperoxidase activity in plasma, IL-6, IL-8, and C-reactive protein levels in serum, and urinary levels of 8-epi-PGF2α and prostaglandin E metabolite (PGEM) in former and never smokers. Serum levels of α-tocopherol, protective against lung cancer, will also be quantified. Collaborative studies with Projects 1 and 3 are also proposed. These innovative studies are expected to provide important new insights on lung cancer mechanisms in former smokers and potentially identify new biomarkers of lung cancer susceptibility.